July 7, 2003

Jo finds genetic factor in vascular plaques

By Holly Korschun

A team of scientists at Emory and Georgia Tech has found a genetic link between mechanical changes in blood flow patterns and the development of atherosclerotic plaques.

The discovery could help explain how increasing blood flow through physical activity helps prevent atherosclerosis.

Hanjoong Jo, a professor in the two schools’ joint Wallace H. Coulter Department of Biomedical Engineering, and his colleagues used a combined engineering and molecular approach to demonstrate how changes in blood flow might contribute to the prevention or development of lipid-containing plaques that can rupture and block blood vessels, leading to heart attack and stroke. The research is published in the online edition of the Journal of Biological Chemistry.

Bioengineers believe that areas of the vascular system with curves, forks and less direct flow are more likely to develop atherosclerotic plaques than areas with straight and unobstructed blood flow. Jo hypothesized that endothelial cells (which line blood vessels) have a biological response to alterations in their mechanical environment. Using a test fluid, he designed a mechanical system to model the patterns made by blood as it flows through the body’s vessels, and then exposed the fluid to aortic endothelial cells of mice.

Through microarray (gene chip) technology, Jo screened 12,000 genes found in the endothelial cells, comparing tissue exposed to a straight and streamlined flow of blood (laminar shear) to tissue exposed to abnormal, non-linear flow patterns (oscillatory shear stress). In the cells exposed to oscillatory shear stress, he discovered a marked increase in expression of the gene that encodes the protein BMP4 (bone-morphogenetic protein-4). In the cells exposed to laminar shear, he found almost no evidence of BMP4.

To further support his results, Jo’s team, in collaboration with Emory cardiologist Robert Taylor and vascular surgeon David Vega, screened endothelial cells from human coronary arteries of patients with atherosclerotic lesions to test for expression of BMP4. BMP4 expression was undetectable in arteries with minimal disease, but it was strongly expressed in endothelial patches found overlying an early form of atherosclerotic lesions called “foam cell lesions.”

Although high blood cholesterol, high blood pressure, smoking and a diet high in saturated fat are known to increase the likelihood of developing heart disease, the risk of physical inactivity is comparable to other factors, according to the American Heart Association.

“The molecular biological response to increases or decreases in blood flow might help us explain why physical inactivity promotes disease,” Jo said. “Increasing one’s heart rate through vigorous exercise causes blood to flow faster through the vessels, and some exercise-related benefits may be due to endothelial expression of certain genes and proteins.”

Jo hopes to use his findings about BMP4 to develop new diagnostic tests or gene-based therapies to prevent plaque formation.

In addition to Taylor and Vega, Jo’s research team of biomedical engineers, cardiologists and surgeons included George Sorescu, Michelle Sykes, Daiana Weiss, Manu Platt, Aniket Saha, Jinah Hwang, Nolan Boyd and Yong Boo.